Background:
- Even in the potentially curative setting, human papillomavirus (HPV)-unrelated head
and neck squamous cell carcinomas (HNSCC) are associated with dismal outcomes
(compared to HPV-related) despite maximal surgical and adjuvant treatment (i.e.,
radiotherapy +/-chemotherapy).
- The window period between diagnosis and curative surgery provides a window of
opportunity to administer therapies that may improve outcomes.
- Four published clinical trials suggest that neoadjuvant checkpoint blockade can
improve recurrence-free survival (RFS) in resectable HNSCC (NCT02919683,
NCT02488759, NCT02296684, NCT04247282). This includes NCI protocol 20C0024
(NCT04247282) where in addition to demonstrating improved 1-year RFS compared to
historical values, our correlative studies provided insight into potential
mechanisms of this benefit.
- N-803 (an IL-15 agonist) combined with anti-programmed cell death protein 1 (PD-1)
therapies work toward maximization of T cell-mediated anti-tumor activity, a key
component of anti-tumor immunity. However, expression of T cell inhibitory receptors
and/or loss of antigen presentation and processing machinery, often driven by T cell
activity s release of interferon-gamma renders some tumor cells invulnerable to T
cell killing.
- Studies conducted by collaborators at the NCI have shown that programmed
death-ligand (PD-L1) t-haNK can lyse such T-cell-resistant tumor cells.
Additionally, in a murine model of oral cancer, the triplet of PD-L1 t-haNK combined
with pembrolizumab and N-803 resulted in more tumor control than the doublet
combinations of these agents.
- PD-L1 t-haNK cells is an allogenic, irradiated (no engraftment), off-the-shelf cell
line currently being studied in combination with pembrolizumab and N-803 in
advanced/metastatic HNSCC (NCI CCR protocol 000096, (NCT04847466)). As of November
2022, 10 participants have been treated and the regimen has been well tolerated.
- In addition to potentially improving outcomes, testing this triplet in the
neoadjuvant setting with pre-and post-treatment tumor biopsies provides an
opportunity to gain insight into the mechanisms of this regimen s anti-tumor
activity.
Objective:
-To determine the pathologic tumor response (pTR) rate (viable tumor in 50% or less of
the surgically resected primary tumor bed) in Arm 1 and Arm 2
Eligibility:
- Histologically or cytologically confirmed previously untreated intermediate/high
risk, p16-negative (if oropharyngeal primary tumor), squamous cell carcinoma of the
head and neck (T1-T4, N0-N3, M0 stage II, III or IV.
- Age >= 18 years.
- Eastern Cooperative Oncology Group (ECOG) performance status <= 1 and adequate organ
function.
Design:
- This is an open-label, single-site, non-randomized, phase II study to evaluate the
efficacy of combined treatment of PD-L1 t-haNK cells, pembrolizumab, and N-803.
- The first 15 participants will be enrolled in Arm 1 and treated with pembrolizumab
and N-803, the following participants will be enrolled in Arm 2 and treated with
pembrolizumab, N-803, and PD-L1 t-haNK cells.
- All participants (Arm 1 and Arm 2) will receive treatment consisting of one
intravenous (IV) infusion of pembrolizumab and one subcutaneous (SC) injection of
N-803 on Day 1.
- Participants in Arm 2 will receive additional treatment with IV infusion of PD-L1
t-haNK cells on Days 1, 5, 8, 12, and 15.
- Participants will be monitored for 2 years.
